Diagnosis of ovarian cancer

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I would like to commend this article which is particularly useful for a non-specialist. As a rheumatologist, I come across a few patients each year with autoimmune forms of myositis, dermatomyositis in particular. Dermatomyositis has a recognised association with ovarian and other forms of cancer, hence my interest in the field. Clinicians should be mindful to examine patients for evidence of muscle weakness (usually proximal) and muscle tenderness, which may indicate the presence of myositis, particularly in the 'red flag' or 'symptoms unrelated to ovarian cancer' patient groups highlighted in the flow-chart. Myositis syndromes are associated with a cluster of other pathologies which include pulmonary fibrosis, oesophagitis, arthritis, rash and digital ischemia, which in addition to making the patient feel very unwell, might also have implications for the choice of therapies available to treat their underlying ovarian cancer.

We thank Hall and Hariharan for their insightful summary on the aetiology of high grade serous ovarian cancer which accounts for about 70% - 80% of all Ovarian Cancer.

Indeed, we ourselves highlighted this in the section ' What are the types of ovarian cancer and why is this important'

To quote directly from the review -

'One important development in recent years is the recognition that the primary source of previously termed “ovarian” cancer is in fact the distal end of the fallopian tube, and seemingly the main site of origin for many high grade serous cancers'.

Our article had the specific remit of educating primary care practioners and non-specialists on the diagnosis of Ovarian Cancer. As such the authors felt this primary purpose would be best served by a focus on symptoms, signs and diagnostic pathways with practical guidance on when to suspect Ovarian cancer in patients with vague symptoms rather than using much of the 2000 word limit on pathology insights that are undoubtedly interesting and relevant but perhaps less practically important for a generalist audience.

We also stress that our remit was 'Diagnosis of Ovarian Cancer', not high grade serous ovarian cancer, and therefore quite broad.

Dear Sir
The excellent recent clinical review on ovarian cancer by Sundar et al missed an important opportunity to highlight our new understanding about the pathogenesis of ‘ovarian cancer’. The fact that most ‘ovary cancers’ arise from the fallopian tube is entirely novel to most doctors (Piek et al, Colgan et al and Shih et al). Single cells escaping directly into the peritoneal cavity elegantly explain the constellation of vague symptoms with which most patients present (Figure 1a). This hypothesis explains the reason for >70% patients presenting at ‘Stage IIIc / IV’ and neatly brings primary peritoneal (high grade serous) cancer into the same fold (simply previously escaped cells from the tube – or peritoneally implanted inclusion cysts from precursor tubal lesions (Carlsson et al, Horn et al)) – after all no reports exist of primary peritoneal cancer in men.
Fallopian tube precursor lesions morphologically and molecularly resemble high-grade ovarian serous carcinoma and are named “serous intraepithelial tubal carcinoma (STIC)”; they are difficult to identify, requiring extensive sectioning (Przbycin et al) and are more commonly found in the distal part of the tube. Given the proximity of the fimbrial end of the tubes to the ovaries, it is acknowledged that such precursor lesions could implant in the surface epithelium of the ovary, forming inclusion cysts and subsequent malignant development in the ovary (Kurman et al). Although many others are likely to escape directly into the peritoneal cavity and are transported around the peritoneal cavity in the ascitic fluid which flows, mostly clockwise Figure 1b (Tan 2013). These malignant cells implant onto the serosa of the peritoneal organs including most commonly the bowel, especially the Pouch of Douglas and rectosigmoid areas, bladder, liver capsule and undersurfaces of the diaphragm, causing the very often vague symptoms, well described by Sundar et al. These also often include bowel dysfunction (constipation and diarrhoea, often incorrectly diagnosed as “irritable bowel syndrome”) and a feeling of early satiety and increasing abdominal distension (or bloating) as the bowel finds it difficult to peristalse effectively when sticking to neighbouring loops.
Further evidence linking “serous tubal intraepithelial carcinoma” (STIC) with ovarian carcinoma is the observation in one series that over 70% of sporadic (nonhereditary) ovarian and peritoneal high-grade serous carcinomas demonstrate mucosal tubal involvement including STICs (Gilks et al 2015) and nearly all STICs, like ovarian cancers, overexpress p53 (Kuhn et al). Extraordinarily, in the same week that Sundar et al have published their article on the diagnosis of ovarian cancer, another Birmingham group (Moss et al) have published a pathological review of all ovarian, tubal and primary peritoneal carcinomas diagnosed in their institution between 2006 and 2012 (Moss et al). Their conclusion is that high grade serous carcinomas whether classified as ovarian, tubal or peritoneal behave as one disease entity with no significant difference in survival outcomes. They propose a separate classification for this group of cancers termed “tubo-ovarian serous carcinoma”.
For this game-changing concept to be understood by medical practitioners who are not in the immediate field but are expected to help make a diagnosis, for example primary care physicians, general gynaecologists, gastroenetrologists and occasionally general surgeons, it is vital to provide a clear visual explanation of the pathogenesis. The omission of such a diagram / picture / cartoon in this article was regrettable and has undoubtedly meant that many hundreds of women will continue to have significant delays in their diagnosis of “tubo-ovarian serous” cancer
Yours faithfully,

Thank you for your email and redrawn figure. We are aware that the NICE guideline figure has limitations and does not flow well. However, we opted to stick to the figure as outlined by NICE largely to maintain consistency with NICE guidance CG122. We are also very aware that GPs are deluged by information and guidance – and felt strongly that consistency with the NICE figure would improve acceptability and uptake by GPs.

We are also conscious that these symptoms are rather vague and for each female patient the GP will have to choose between one of several cancer referral pathways.

We congratulate the authors for a succinct presentation and acknowledge the points raised. In the interest of accuracy, we point out clinical errors:

Referral to rapid access clinic not gynaecological oncology.
Current Guidance is not restricted to women over 50.

This article is interesting and illuminating but the NICE Flow Chart [1] in the Figure is poorly organised and contains multiple errors making it difficult to understand and use, and the authors' changes add no value to it.

The flaws in the Flow Chart are as follows :-

1. The horizontal choices emanating from the “GP Consultation” Box are not mutually exclusive and encourage incorrect data flow from left to right instead of from top to bottom ( Figure 6 [2] ). The Flow Chart does not follow the order of the traditional diagnostic process namely History, Examination and Investigations followed by Diagnosis/Differential Diagnosis. Moving from left to right, the subject of the first Box is “Examination Findings”, the next two Boxes, “History Items”, and the last, “Unrelated Symptoms”. This last Box adds no value to the Flow Chart and should be omitted. A similar error can be found in a Flow Chart for the diagnosis of syncope [3].

2. The two “Symptoms” Decision Boxes should be combined into one Box as their outputs converge ( q.v. Figure 1 ).

3 .The two “Symptoms” Decision Boxes have no “Yes” and “No” choices
( i.e. Does the patient have any of these symptoms? ) so how can one select a valid response to the Decision Box containing the question immediately following them " Is ovarian cancer suspected?" which does have these choices?

4. The Decision and Process Boxes in the Flow Chart are of the same shape ( rectangular ) rather than decisions being placed in diamond-shaped boxes and processes in rectangular boxes.

5. The Decision Box based on the result of the “ultrasound of the abdomen and pelvis” should have a further Decision Box attached to it if the result is abnormal but not ovarian cancer ( q.v. Figure 1 ).

6. The decision process in the Flow Chart is cyclical and this property is not evident in the original Chart.

Figure 1 shows our re-designed Flow Chart that corrects the deficiencies in the original one. The Yellow Process Boxes indicate the possible end points of the Flow Chart. We have not included all the symptoms in the first Decision Box of the Flow Chart for the sake of clarity.

We thank Crawford and Gajjar for their interest in our paper. In response

We agree that as more information on genetic predisposition comes to light that the oncology and genetic community and the population as a whole will need to prepare for engagement with genetic testing. However, it is important in doing so that we fully engage with the public, stakeholders and care providers to articulate a strategy for genetic testing that is acceptable to the public, affordable and sustainable Vis a vis service demand. The NHS is piloting/gradually introducing reflex testing for Ovarian Cancer based on large genomic studies demonstrating >17% prevalence of BRCA mutations in High grade Serous Ovarian Cancer. This is as yet not fully embedded in NHS practice.

As Crawford and Gajjar emphasise, we are resolutely in support of symptom triggered testing for Ovarian Cancer and agree that a shift from diagnosis through emergency presentation to GP referral has the potential to improve mortality, particularly within the first 12 months after diagnosis.

On the subject of genetic testing, we note that the poster that Crawford and Gajjar cite is not yet in public domain. Thus we are unable to comment on the data supporting an 11% risk of BRCA mutation in an unselected (presumably low risk) population. We certainly await the full publication of the GTEOC study results with interest. This would need careful scrutiny prior to presentation of evidence to the National Screening committee and relevant stakeholders.

We apologise for the typo – as Crawford and Gajjar point out we do indeed mean Salpingectomy and ‘delayed oopherectomy’. We agree that this is still within the sphere of research 2 and should not be routinely considered.

Very good article!
But some confusion over the CA125 results. In an earlier paragraph, units are expressed in IU/L (>35) and a later offering reported as units/ml (>200). Please clarify the discrepancy?

We greatly enjoyed reading the article by Dr Sundar et al from Birmingham aimed at primary care and hospital doctors in other specialties. In the "Bottom line" section, we feel that all women under the age of 70 should be offered genetic testing for BRCA mutations as more than 11% in unselected population will be positive (1). There is a need for appropriate integration with existing oncology and genetic services for this to occur in the UK in a timely fashion.

We support the investigation of women in primary care who have the constellation of symptoms described even if this leads to increased referrals and more investigation. These women are concerned and worried about their symptoms and the investigations go some way in reducing their anxiety about a cancer diagnosis as well as giving reassurance. We are only too aware of the poor outcome for patients presenting to emergency department who have a 45% as compared to 84% 1 year survival of those seen in two week wait or rapid access clinic (2) and whilst we await better diagnostic tools such as circulating tumour cells and the ROCKETS study outcome we must do something positive.

There is a typographical error in the paragraph relating to recommendations for women with a known genetic predisposition. The alternative strategy proposed is laparoscopic salpingectomy and delayed oophorectomy ( not delayed salpingectomy as written). This strategy is theoretically sound based on the tubal theory for the evolution of the high grade serous ovarian carcinoma seen in BRCA mutations. This leaves the woman with a possibility of further fertility via assisted reproduction and avoids the menopause. However, discussion about this approach and the length of time before removal of the ovaries needs to be with specialist gynaecological genetic clinics and is not for the piece meal introduction without an evidence base.

We read with great interest the patient’s perspective. It highlighted several points very well. There needs to be a greater awareness in primary care and the public that there are familial predispositions to cancer and that these can be investigated whether using computer based programmes such as BOADICEA by health care providers (3). Secondly, the woman/patient was a victim of the old fashioned approach of “no news is good news”. Ideally all results from tissue removed should be communicated to both patient and general practitioner in a timely fashion.

In respect of the prevention or delay of recurrence of ovarian cancer after treatment and remission there is anecdotal evidence that a daily intake of palmitoyl ascorbate (a safe food additive) can reduce the CA125 count and extend the periods of remission.

This is worthy of further research as the compound is cheap (<10 p / day) and freely available. Perhaps a group might feel able to consider it with a view to saving NHS funds.